Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery

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RFS [ Time Frame: From randomization to the time of disease recurrence or death from any cause, assessed up to 20 years ]

Will be performed using the log-rank test. Kaplan-Meier plot will be generated and two-sided p-values will be reported. If the proportional hazard assumption is appropriate, multivariate Cox proportional hazard models for RFS will be developed at the final analysis. For the stratified log-rank test and Cox proportional hazards regression model, sensitivity analysis will be conducted at the final analysis based on analyzable (eligible and treated) patients only.

OS [ Time Frame: From randomization to date of death, assessed up to 20 years ]

Will be performed using the log-rank test. Kaplan-Meier plot will be generated and two-sided p-values will be reported. If the proportional hazard assumption is appropriate, multivariate Cox proportional hazard models for OS will be developed at the final analysis. For the stratified log-rank test and Cox proportional hazards regression model, sensitivity analysis will be conducted at the final analysis based on analyzable (eligible and treated) patients only.

Incidence of toxicity assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 70 days after completion of study treatment ]

Will be summarized by treatment group and NCI CTCAE worst grade. Toxicity incidence rate and 95% confidence interval for each type will be presented. The percentages of patients experiencing the worst degree toxicities (highest grade event per adverse event [AE] type per patient) will be evaluated and the distribution of the worst degree toxicities will be compared among the treatment arms. The proportion of patients with worst degree toxicities with 3 or higher will be summarized and compared among the treatment arms. Chi-square test will be used for AE comparisons.

Change in global quality of life assessed using the FACT-G (patients age >= 18 only) [ Time Frame: Baseline to up to 1 year ]

The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.

Change in health-related domains of quality of life assessed using symptom and functioning subscales (patients age >= 18 only) [ Time Frame: Baseline to up to 1 year ]

The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.

This randomized phase III trial studies ipilimumab to see how well it works compared to high-dose interferon alfa-2b in treating patients with high-risk stage III-IV melanoma that has been removed by surgery. Monoclonal antibodies, such as ipilimumab, may interfere with the ability of tumor cells to grow and spread. Interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of melanoma and other cancers. It is not yet known whether ipilimumab is more effective than interferon alfa-2b in treating patients with melanoma.

II. To evaluate overall survival (OS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (HIP) or 3 mg/kg (LIP) versus those randomized to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant).

SECONDARY OBJECTIVES:

I. To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP).

II. Among patients enrolled by Clinical Community Oncology programs (CCOPs), to compare the global quality of life (QOL) between the ipilimumab arms versus HDI using Functional Assessment of Cancer Therapy (FACT)-General (G) form and to evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of QOL using Functional Assessment of Chronic Illness Therapy (FACIT)-diarrhea (D) and FACT-biological response modifiers (BRM).

OUTLINE: Patients age >= 18 are randomized to Arms A, B, or C and patients ages 12-17 are randomized to Arms D, E, or F.

ARM A: Patients receive induction high-dose ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (closed accrual as of 4/4/14) (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

ARM B: Patients receive induction high-dose recombinant interferon alfa-2b IV over 20 minutes on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance high-dose recombinant interferon alfa-2b subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

ARM C: Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

ARM D: Patients receive induction high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity.

ARM E: Patients receive induction high-dose recombinant interferon alfa-2b IV over 20 minutes on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance high-dose recombinant interferon alfa-2b SC on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity

ARM F: Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for up to 15 years.

Patients receive induction high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (closed accrual as of 4/4/14) (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

Interventions:

Biological: Ipilimumab

Other: Quality-of-Life Assessment

Experimental: Arm B (age >= 18, recombinant interferon alfa-2b)

Patients receive high-dose recombinant interferon alpha-2b IV on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance high-dose recombinant interferon alpha-2b SC on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

Interventions:

Other: Quality-of-Life Assessment

Biological: Recombinant Interferon Alfa-2b

Experimental: Arm C (age >= 18, low-dose ipilimumab)

Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

Interventions:

Biological: Ipilimumab

Other: Quality-of-Life Assessment

Experimental: Arm D (age 12-17, high-dose ipilimumab)

Patients receive induction high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity.

Intervention: Biological: Ipilimumab

Experimental: Arm E (ages 12-17, recombinant interferon alfa-2b)

Patients receive high-dose recombinant interferon alpha-2b IV on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance high-dose recombinant interferon alpha-2b SC on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity. (ages 12-17)

Intervention: Biological: Recombinant Interferon Alfa-2b

Experimental: Arm F (ages 12-17, low-dose ipilimumab)

Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (ages 12-17)

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE

Active, not recruiting

Estimated Enrollment ICMJE (submitted: June 24, 2016)

1500

Original Estimated Enrollment ICMJE (submitted: January 8, 2011)

900

Study Completion Date

Not Provided

Estimated Primary Completion Date

May 1, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria ICMJE

Inclusion Criteria:

All patients must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization; imaging studies must include a total body positron emission tomography (PET)-computed tomography (CT) scan (with or without brain) and brain magnetic resonance imaging (MRI) or CT (if MRI is contraindicated); if PET-CT cannot be done, CT of neck, chest, abdomen, and pelvis should be done

If for some reason a CT cannot be done, an MRI may be done instead; any other imaging studies if performed (eg, bone scan) must show no evidence of disease

Patients must have primary cutaneous melanoma that belong to one of the following American Joint Commission on Cancer (AJCC) stages (2009 AJCC Melanoma Staging System):

Stage IIIB

T1-4b N1a M0

T1-4b N2a M0

T1-4b N1b M0

T1-4b N2b M0

T1-4b N2c M0

Stage IIIC

T1-4b N1b M0

T1-4b N2b M0

T1-4b N2c M0

Any T N3 M0

Stage IV

M1a

M1b

NOTE: patients with stage IV melanoma must have normal lactate dehydrogenase (LDH) and either distant skin, subcutaneous, lymph node, or lung metastases, but no other visceral metastases in order to be eligible; for patients with resected stage IV melanoma, LDH within the institutional upper limit of normal (ULN) must be documented within 4 weeks prior to randomization

Patients with disease recurrence after adequate surgical excision of the original primary cutaneous/unknown primary melanoma are allowed even if they don't fit the strict staging criteria, but only as follows:

Patients with unknown primary melanoma (Tx) who present with cutaneous, subcutaneous, nodal and/or lung metastases that are completely surgically resected with free margins are allowed; these patients are allowed even if they don't fit the strict staging criteria; for stage IV patients LDH within the institutional ULN must be documented within 4 weeks prior to randomization (M1c is not eligible)

NOTE: all subjects should be classified as IIIB, IIIC, M1a or M1b including subjects with disease recurrence after adequate surgical excision of the original primary melanoma; that is the treating team/physician investigator should review an overall TNM status (that includes primary tumor presentation and disease recurrence status) and provide a designation of IIIB, IIIC, M1a or M1b

Patients must be randomized within 84 days (12 weeks) of surgical resection; if more than one surgical procedure is required to render the patient disease-free, the patient must be randomized within 12 weeks of the last surgery

NOTE: patients with clinically positive lymph nodes for melanoma involvement or those with positive lymph nodes identified through lymphoscintigraphic and/or dye lymphographic techniques in the groin, axilla, or neck should have additional lymphadenectomy in those sites; the complete lymph node dissection procedure would be considered as the last surgery in counting the 84 days unless a subsequent surgical procedure(s) was clinically required to ensure the disease free status

Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after the resection(s) that make(s) them eligible for this trial

NOTE: previous radiation therapy, including after the surgical resection, is allowed as long as 21 days have elapsed between the radiation and initiation of this adjuvant systemic therapy

Prior treatment with anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) monoclonal antibodies or prior CTLA-4 inhibitor or agonist or prior clusters of differentiation (CD)137 agonist or prior interferon-alfa is not allowed; other forms of prior treatment for melanoma (e.g., aldesleukin [IL-2], anti-tumor vaccine, chemotherapy) are allowed if given before the resection(s) that make(s) the patient eligible for this trial, but these must have been completed at least 4 weeks prior to randomization

Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

Patients must not have an active infection requiring current treatment with parenteral antibiotics

Patients must not have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that in the opinion of the investigator may interfere with compliance, make the administration of ipilimumab or HDI hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea; patients with a baseline of frequent diarrhea (e.g. irritable bowel syndrome) are not eligible

Patients should be carefully screened for depression at baseline and if there are indications or a history of depression it is strongly recommended that these patients be closely followed together with behavioral health or psychiatric medical support; patients with an established diagnosis of depression that, in the assessment of the investigator may make the administration of interferon (IFN)-alfa or ipilimumab hazardous, should not be enrolled on this protocol; the risks and benefits of being treated with standard adjuvant IFN-alfa should be weighed very carefully in consultation with behavioral health or psychiatry

Patients must not have a documented history of inflammatory bowel disease (including ulcerative colitis and Crohn's disease) or diverticulitis (history of diverticulosis is allowed)

Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids; a history of occasional (but not continuous) use of steroid inhalers is allowed; replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study

Patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible

Patients must not have had any infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, meningococcal, or tetanus toxoid) within 4 weeks prior to randomization

Patients must not be prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

Patients who have other current malignancies are not eligible; patients with other malignancies are eligible if they have been continuously disease free for > 5 years prior to the time of randomization; patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ are eligible; patients with prior history of basal or squamous skin cancer are eligible; patients who have had multiple primary melanomas are eligible

Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study during screening to rule out pregnancy

NOTE: a woman of childbearing potential (WOCBP) is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); post-menopause is defined as:

WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of ipilimumab or HDI, in such a manner that the risk of pregnancy is minimized; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential

Men of fathering potential and WOCBP must be using an adequate method of contraception to avoid conception/pregnancy throughout the study and for up to 26 weeks after the last dose of ipilimumab or HDI in such a manner that the risk of pregnancy is minimized; men or WOCBP who are unwilling or unable to strictly follow this requirement are not eligible